This invention relates to the use of a phosphinate protecting group to stabilize thyroxine and related compounds, thus extending the shelf life of the drugs.
Hypothyroidism is the most common disorder of the thyroid and is manifested through the thyroid gland""s inability to produce sufficient thyroid hormone, primarily 3, 3xe2x80x2, 5-triiodothyronine (also known as T3). Symptoms associated with hypothyroidism include cold intolerance, lethargy, fatigue, chronic constipation and a variety of hair and skin changes. Although none of these conditions are life threatening, the disease, left untreated, could result in myxedema, coma, or death.
The cause of hypothyroidism in the U.S. is brought about by either autoimmune destruction of the thyroid tissue (Hashimoto""s disease), 131I therapy, or ablative surgery. It is estimated that 8 to 10 million people in the United States have low thyroid gland function, but only about 4 to 5 million hypothyroid cases have been diagnosed and treated. The prevalence of hypothyroidism increases with age, particularly within the female population.
The modern history of thyroid medication starts in the 1890""s when desiccated pig thyroid was used to treat hypothyroidism. Thyroxine (3,3xe2x80x2,5,5xe2x80x2-tetraiodothyronine), also known as T4, was introduced over forty years ago as a means to deliver the T3 hormone slowly without subjecting the patient to a transient hyperthyroid state. A synthetic drug based on blending T3 with T4 in a biomimetic fashion was introduced as an improved version. The medical community has discouraged this regimen, however, due to its potential for life-threatening T3 spikes.
More recently, Synthroid, a synthetic T4 compound, has captured more than 70% of the hypothyroidism market. Synthroid""s sales are reported to be in excess of $500 million (with additional sales in the market being taken by generic versions of thyroxine).
Although T4 is a safe and effective way to treat hypothyroidism, a potential problem exists. Sufficient data has been generated that shows that Synthroid has a relatively short shelf life. The FDA has recommended that manufacturers of thyroid drugs address this problem.
U.S. Pat. No. 5,225,204 is directed to improving the stability of levothyroxine sodium. This patent indicates that the stability of the levothyoxine is affected by the presence of some carbohydrate excipients, such as dextrose, starch, sugar, and lactose. This patent claims that stability is achieved through mixing the levothyroxine with a cellulose carrier, with or without the addition of either polyvinyl pyrrolidine (PVP) or a Poloxamer.
U.S. Pat. No. 5,955,105 is also directed to providing an improved, stable, solid dosage form of thyroid hormone pharmaceutical preparations. This patent claims pharmaceutical preparations of thyroxine drugs including a water soluble glucose polymer and a partially soluble or insoluble cellulose polymer to provide the stability. The indicated stability is determined as an absence of potency loss when the preparation is stored at 40 degrees C. and 75% relative humidity for six months. U.S. Pat. No. 5,955,105 is hereby incorporated by reference, particularly for its teachings on components of and production of pharmaceutical preparations of thyroxine drugs.
It has been reported that the major product of T4 decomposition is diiodotyrosine (DIT). Latham, et al., showed that T4 in the blood decomposes into quinone-containing molecules. Both of these reports lead to the conclusion, heretofore unreported, that the pathway for T4 decomposition goes through a hydrolysis step with the loss or cleavage of an iodide. The energy required to cleave an sp2-hybridized iodide-carbon bond, as in the case of T4, is not available under ambient conditions. As shown in FIG. 1, tautomerization prior to hydrolysis is required in order for T4 to decompose into DIT and iodoquinone. In other words, the spontaneous tautomerization of T4 is the xe2x80x9ctriggerxe2x80x9d for its decomposition.
The energy required to cleave a phosphorus-oxygen bond is greater than that for breaking a hydrogen-oxygen bond. The utility of the present invention resides in the prevention of tautomerization by replacing the hydrogen on the phenolic hydroxyl with a phosphinate group. By preventing tautomerization (as shown in FIG. 3), the hydrolysis step cannot take place, thereby, reducing the lability of T4 to hydrolysis and increasing its shelf life.
The dimethylphosphinate group has been used as a protecting group for tyrosine in peptide synthesis. Ueki et al., Tetrahedron Letters 27(35):4181-4184 (1986). The purpose of this group, however, was only to offer protection during peptide synthesis. It was not used to stabilize any other compounds, and was used only as part of a step during synthesis, never as a compound for use as a pharmaceutical composition. One aspect of the present invention is that it was not heretofore appreciated that stabilization was necessary in thyroid hormones. This problem is herein both recognized and solved by the use of phosphinate (and possibly other) protecting groups on the phenolic hydrogen. The resulting protected hormone is not deprotected in vitro. Rather, the hormone or hormone precursor is ingested while still protected by the phosphinate group.
The result of the present invention is a prodrug to a thyroid hormone, which will be converted to the thyroid hormone in vivo after being provided to the patient in a hypothyroidism treatment regimen. The prodrug will be hydrolyzed in the stomach or the gut into thyroxine and the biologically inert dimethylphosphinic acid. This provides a drug with all the therapeutic advantages of Synthroid with the additional advantage of increased stability, i.e., longer shelf life. Another advantage is that a thyroxine product with increased stability will be useful in producing either an injectable product or an oral suspension (suitable for children)xe2x80x94both of which are desirable. Yet another advantage of the present invention is a method to stabilize and increase the shelf life of thyroxine and related thyroid hormone compounds.
The compounds of the present invention may be provided in several useful forms, including pharmaceutical compositions in the form of ingestable tablets, oral suspension, or intravenous solutions.